Pro-opiomelanocortin (POMC) derived peptides are known to affect food intake. There also exists evidence that the G-protein coupled receptors of the melanocortin receptor (MC-R) family are targets of POMC derived peptides involved in the control of food intake and metabolism. The melanocortin receptors may therefore be viable targets for the control of obesity.
At least five MC-Rs have been identified, and these receptors are expressed in different tissues. MC-1R is primarily expressed in melanocytes [Chhajlani, V.; Wikberg, J. E., FEBS Lett., 309 (1997) 417-420; Mountjoy, K. G. et al., Science, 257 (1997) 1248-1251]. MC-2R is expressed in the adrenal cortex and represents the ACTH receptor [Mountjoy, K. G. et al., Science, 257 (1997) 1248-1251]. MC-3R is expressed in the brain, gut, and placenta and may be involved in the control of food intake and thermogenesis. MC-4R, is a seven-transmembrane receptor which is expressed in the brain, and its inactivation has been shown to cause obesity [Huszar, D. et al., Cell, 88 (1997) 131-141]. MC-5R is expressed in various tissues including white fat, placenta, exocrine glands and brain and inactivation of this receptor results in decreased production of lipids from the sebaceous glands which in turn effects thermoregulation [Chen, W. et al., Cell, 91 (1997). 789-798].
Evidence for the involvement of MC-Rs in obesity includes the agouti mouse. The viable yellow (Avy) variants of agouti mice express the agouti protein, both ectopically and within the hair follicle, which acts as an antagonist of the MC-1R, MC-3R, and MC-4R. These mice are characterized by maturity-onset obesity, hyperinsulinemia, hyperglycemia in males, yellow coat color, hyperphagia, increased rates of hepatic lipogenesis and decreased rates of lipolysis in adipocytes [Yen, T. Y. et al., The FASEB J, 8 (1994) 479-488] and references therein) indicating that blocking the action of the MC-1R, MC-3R, and MC-4R can lead to the characteristics of the pleiotropic obesity syndrome. MC-4R knockout mice exhibit the same phenotype as the agouti (Avy) mice and have other characteristics of the pleiotropic obesity syndrome described above [Huszar, D. et al., Cell, 88 (1997) 131-141]. Rodents injected intracerebroventricularly (ICV) with the cyclic heptapeptide melanotan-II (MT-II), a MC-1R, -3R, -4R, -5R agonist, have reduced food intake in several animal feeding models (NPY, ob/ob, agouti, fasted) while ICV injected SHU-9119, a MC-3R, -4R antagonist and MC-1R, -5R agonist, reverses this effect and can induce hyperphagia [Nargund, R. et al., WO 99/64002, published Dec. 16, 1999]. Additionally, chronic intraperitoneal treatment of Zucker fatty rats with an α-NDP-MSH derivative (HP228) has been reported to activate MC-1R, -3R, -4R and -5R and to attenuate food intake and body weight gain over a 12 week period [Nargund, R. et al. WO 99/64002, published December 16, 1999].
Melanocortin receptors may also be viable targets for the control of certain types of sexual dysfunction. Intramuscular administration of melanotan-II (MT-II) within a dose range of 0.005-0.03 mg/kg caused intermittent non-painful penile erections in three normal male volunteers for a period of 1-5 hours after dosing [Dorr et al., Life Sciences, 58(20) (1996) 1777-1784]. Subcutaneous administration of MT-II (0.025 mg/kg and 0.1 mg/kg) to 10 patients with psychogenic erectile dysfunction caused transient erections (8 responders) with onset from 50-180 minutes [Wessells, H. et al., J. Urology, 160 (1998) 389-393].
Spiropiperidine derivatives, of the following general Formula (i), which act as melanocortin receptor agonists were disclosed by Nargund et al. in WO 99/64002 (published on Dec. 16, 1999). 
Piperidine derivatives of general Formula (ii) which act as selective melanocortin-4 receptor agonists useful for the treatment, control or prevention of obesity, diabetes and sexual dysfunction were disclosed by Bakshi, et al. In WO 00/74679 (published on Dec. 14, 2000). 
Serine derivatives, described as useful for the treatment or prevention of pain, inflammation, migraine, emesis and postherpetic neuralgia were disclosed by Elliott et al. in U.S. Pat. No. 5,885,999 (issued Mar. 23, 1999). These derivatives are of the general Formula (iii), shown below, wherein m is 0, 1, or 2; and n is 0 or 1, with the proviso that the sum of m and n is 1 or 2; R1 represents phenyl, napthyl, benzhydryl or benzyl; R2 represents hydrogen, phenyl, napthyl, benzhydryl, benzyl, indazolyl, thienyl, furanyl, pyridyl, thiazolyl, tetrazolyl and quinolinyl; R3 and R4 each independently represent hydrogen or C1-6alkyl, or R3 and R4 together are linked so as to form a C1-3 alkylene chain; Q represents CR5R6 or NR5; X and Y each independently represents hydrogen, or together form a group ═O; and Z represents a bond, O, S, SO, SO2, NRc or —(CRcRd)—, where Rc and Rd each independently represent hydrogen or C1-6alkyl.
These reference compounds are distinguished structurally from the compounds of the instant invention by virtue of these art compounds containing an amide or serine linked substituted piperidine moiety whereas the compounds of the instant invention contain a tyrosinamide linked substituted piperazine moiety. The novel compounds of the present invention have also been discovered to possess melanocortin receptor activity, thus, the prior art does not disclose nor suggest the unique combination of structural fragments which embody these novel tyrosinomide derivatives as having good activity at melanocortin receptor sites.